DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Application Status
Claims 1-4 are pending.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-4 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP 2163.II.A3.(a).(i) states, “whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
For claims drawn to a genus, MPEP 2163.II.A3.(a).(ii) states, “written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species” where “representative number of species' means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.”
Claim 1 recites “a ETV6 or ETV3 inhibitor”, which represents a genus of molecules that are defined by their function of inhibiting the expression or activity of the ETV3 or ETV6 proteins (Specification, ¶ spanning pages 9-10). Some such inhibitors are described in the specification on pages 10-11, including “a small organic molecule” and “a siRNA, a antisense oligonucleotide of a ribozyme”.
Regarding siRNA and antisense oligonucleotides, the expressed transcript sequences of ETV3 and ETV6 are well known. Because there is a known correlation between the structure of antisense molecules and their inhibitory function, one skilled in the art could have predicted the structure of antisense and siRNA molecules that have the claimed inhibitor function. However, for the reasons described below, Applicants have not sufficiently described the genus of inhibitors that are antibodies, small organic molecules, or ribozymes that have the claimed ETV3 or ETV6 inhibitory function such that one skilled in the art could have reasonably concluded applicants had possession of the genus as claimed.
Regarding antibody-based inhibitors, the instant specification in view of the art must structurally describe representative ETV3 or ETV6 antibodies that function as an inhibitor, or describe structural features common to the members of the genus, which features constitute a substantial portion of the genus. Alternatively, the specification can show that the claimed invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics (see University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) and Enzo Biochem, Inc. V. Gen-Probe Inc.). However, in this case the Specification is completely silent on possible ETV3 or ETV6 antibodies that function to inhibit ETV3 or ETV6 in vivo. A few ETV3 or ETV6 antibodies are commercially available that can be used to detect ETV3 or ETV6 by western blot, immunofluorescence or immune-histochemistry, e.g., the Specification cites to ETV6/TEL and ETV3 antibodies from Novus Biologicals (page 15). However, the Specification nor the companies do not provide the structure of the ETV6/TEL and ETV3 antibodies. Additionally, none of the commercially available ETV6/TEL and ETV3 antibodies are disclosed as capable of functioning in cells or in vivo.
Regarding small organic molecules, although the Specification recites that small organic molecules can be used (page 10), the Specification does not provide examples of ETV3- and ETV6-specific small molecule inhibitors. A diligent search of the prior and contemporaneous art revealed no teachings of any molecules known to inhibit ETV3 or ETV6. Small molecule inhibitors of related family member ERG have been developed (e.g., VPC018005); however, there is no evidence in the art that they can also inhibit ETV3 or ETV6 function. Around the time of the filing date, skilled artisans understood that discovering inhibitors of proteins generally was unpredictable. Wu observes that although computer-aided protein-inhibitor discovery technology was available, there is insufficient data to predict inhibitors of many proteins (Wu et al., Molecules (2019), 24: 4428). Wu writes: [U]nder many circumstances, it is hard to find a [compound] library with functionally and structurally diverse molecules with quantitative activity data for a given protein. More importantly, the lack of publications with negative results hinders the identification of inactive molecules, resulting often in the development of qualitative common feature pharmacophores only from active compounds. Finally, as LBVS applications are generally based on the properties of the known ligands, the diversity of the hits discovered are generally limited. (Page 3 of 14, second paragraph.)
Regarding ribozymes, the Specification dose not provide any example or structure of an RNA-based enzyme (i.e., a ribozyme) that can inhibit the function of ETV3 or ETV6 or their expression. Unwalla teaches ribozymes cleave phosphodiester backbones of targeted mRNAs (Unwalla and Rossi, "Screening effective target sites on mRNA: a ribozyme library approach." Ribozymes: Methods and Protocols. Totowa, NJ: Humana Press, 2012. 329-336; page 329, ¶1). Unwalla teaches that randomizing the hybridizing arms of a hairpin or hammerhead RNA motif is necessary to screen for ribozymes with the intended effect (page 330). Thus, it appears that there is not a predictable relationship between the sequence sequence/structure of a ribozyme and its function to target a specific gene like there is for siRNA inhibitors. A diligent search of the prior and contemporaneous art revealed no teachings of any ribozymes that specifically target ETV3 or ETV6-encoding mRNAs.
Although Applicants may argue that it is possible to screen for ETV3 or ETV6 antibodies, small molecules and/or ribozymes that function as claimed, the court found in that screening assays are not sufficient to provide adequate written description for an invention because they are merely a wish or plan for obtaining the claimed chemical invention. Rochester v. Searle, 358 F.3d 916, Fed Cir., 2004. “As we held in Lilly, “[a]n adequate written description of a DNA … ‘requires a precise definition, such as by structure, formula, chemical name, or physical properties,' not a mere wish or plan for obtaining the claimed chemical invention.” 119 F.3d at 1566 (quoting Fiers, 984 F.2d at 1171). For reasons stated above, that requirement applies just as well to non-DNA (or RNA) chemical inventions.” Knowledge of screening methods provides no information about the structure of any future ETV3 or ETV6-specific antibodies, small molecules and ribozymes yet to be discovered that may function as claimed.
Given the lack of representative examples to support the full scope of the ETV3 or ETV6 inhibitors encompassed by the claim, and lack of reasonable structure-function correlation with regards to the unknown sequences of ETV3 or ETV6 antibodies, small organic molecules and ribozymes that provide can inhibit Etv3 and Etv6 function, the specification does not provide an adequate written description of molecules that inhibit ETV3 or ETV6 function that is required to practice the claimed invention.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-2 and 4 are rejected under 35 U.S.C. 103 as being unpatentable over Marzaioli (Marzaioli et al., Blood (2017), 130: 1734-1745), in view of Lau (Lau et al., Journal of Experimental Medicine (2018), 215: 2265-2278), Goudot (Goudot et al., Immunity (2017), 47: 582-596), Fisher (Fisher et al., JCI insight (2020), 5(18), e140332) and Hu (Hu et al., Signal Transduction and Targeted Therapy (2020), 5:101, pages 1-25).
Regarding claims 1-2 and 4, Marzaioli teaches inflammatory dendritic cells (DCs) are derived from monocytes and can be referred to as monocyte-derived dendritic cells (Mo-DCs) (page 1734, ¶1). Marzaioli teaches during infection, circulating monocytes emigrate from bone marrow into circulation where they differentiate into DCs, which then maturate and acquire T-cell stimulatory functions (page 1734, ¶1). Marzaioli teaches limiting differentiation of monocytes into Mo-DCs could be a beneficial strategy to treat human inflammatory diseases (¶ spanning pages 1734-1735). Marzaioli teaches the activity of NOX5 promotes Mo-DC differentiation (Fig 7). Marzaioli teaches administering siRNAs (i.e., an inhibitor) targeting NOX5 reduces Mo-DC differentiation (Fig 4E, page 1741, ¶1).
Marzaioli does not teach providing an siRNA targeted to ETV6 or ETV3 for the purpose of inhibiting Mo-DC differentiation.
Lau teaches the ETV6 transcription factor regulates differentiation of dendritic cells (Title). Lau teaches that ETV6 is expressed primarily in DCs and monocytes (page 2266, ¶3). Lau teaches knocking out ETV6 specifically in bone marrow cells impaired differentiation of DC cells (page 2266, ¶5).
Goudot teaches that ETV6 is highly expressed in Mo-DCs, but not monocyte-derived macrophages (Fig 2).
Fisher teaches treating peripheral blood mononuclear cells (PBMCs) (i.e., including monocytes) with an siRNA targeting ETV6 (page 3, ¶2; page 11, ¶1).
Hu teaches the state of the art of siRNA therapies as of 2020 (Title). Hu teaches several siRNA therapies have FDA and EC approval (page 1, ¶3). Hu teaches that siRNAs can be formulated for targeted in vivo delivery (throughout).
Regarding claims 1, 2 and 4, it would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have used Fisher’s siRNA in Marzaioli’s method of inhibiting Mo-DC differentiation specifically in a subject suffering from an inflammatory disease. It would have amounted to the simple combination of elements by known means to yield predictable results. Starting from Marzaioli and looking for alternative approaches to block the differentiation of monocytes into dendritic cells, the skilled person would have been motivated to use an ETV6 inhibitor, since Lau teaches ETV6 was known to be required for the differentiation of dendritic cells and Goudot teaches upregulation of ETV6 during monocyte-to-DC differentiation but not monocyte-to-macrophage differentiation. The skilled artisan would have predicted that an ETV6 siRNA could be delivered to a patient because Fisher teaches delivering siRNA to bone-marrow derived cells and Hu teaches that siRNA-delivery is well known in the art.
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Marzaioli (Marzaioli et al., Blood (2017), 130: 1734-1745), Lau (Lau et al., Journal of Experimental Medicine (2018), 215: 2265-2278), Goudot (Goudot et al., Immunity (2017), 47: 582-596), Fisher (Fisher et al., JCI insight (2020), 5(18), e140332) and Hu (Hu et al., Signal Transduction and Targeted Therapy (2020), 5:101, pages 1-25), as applied to claims 1-2 and 4 above, and further in view of Wu (Wu and Laufer, Current Neurology and Neuroscience Reports (2007), 7: 245-252).
The teachings of Marzaioli, Lua, Goudot, Fisher and Hu are recited above and applied as for claims 1-2 and 4. Hu also teaches central nervous system (CNS)-targeted siRNA delivery platforms have been established (page 20, ¶3).
Marzaioli, Lua, Goudot, Fisher and Hu do not teach the role of dendritic cells in multiple sclerosis (MS).
Wu teaches the clinical and pathological features of MS point to an immune-mediated pathogenesis (page 245, ¶1). Wu teaches that DCs are ultimately culpable for the generation of autoreactive T-cell activity in MS (page 245, ¶1). Wu teaches there is an increased abundance of DCs in the CNS of MS patients (page 248, ¶2). Wu teaches in MS patients, monocyte-derived DCs secrete IL-23, which in turn support Th-17 polarization of T cells (page 248, ¶4).
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have used the ETV6-targeted siRNA treatment method rendered obvious above specifically to prevent DC differentiation from monocytes in MS patients. It would have amounted to modifying a known siRNA for delivery to circulation and CNS by known means for treatment of a disease that is known to have a monocyte-derived DC pathological component. The skilled artisan would have been motivated to specifically treat MS patients since it was well established that DCs play a role in MS pathology. It was entirely predictable that siRNAs targeting ETV6 could be administered to MS patients for the purpose of reduced monocyte-derived DC differentiation because Hu teaches siRNA delivery means to both systemic circulation and the CNS have been developed.
Conclusion
No claims are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CATHERINE KONOPKA whose telephone number is (571)272-0330. The examiner can normally be reached Mon - Fri 7- 4.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Ram Shukla can be reached at (571)272-0735. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CATHERINE KONOPKA/Primary Examiner, Art Unit 1635
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